Yubin Peng1,2,3
Tao Wang1,2,3*- 1Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- 2State Key Laboratory of Complex Severe and Rare Diseases, Beijing, China
- 3National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China
A Commentary on
Local sympathetic nerve depletion does not alter vitiligo progression in a mouse model
by Hu, Z., Chen, T., and Chen, D. (2025). Front. Med. 12:1466996. doi: 10.3389/fmed.2025.1466996
1 Introduction
The recent article by Hu et al. has challenged the existing hypothesis regarding the potential pathogenic role of sympathetic nerves in vitiligo. Their study randomized mice into two groups: a chemical sympathectomy group, which underwent sympathetic denervation via 6-hydroxydopamine (6-OHDA), and an untreated control group. Both groups were subsequently induced with vitiligo using the melanoma–regulatory T cell (Treg)-induced vitiligo model. Epidermal melanocytes and CD8+ T cells of tail skin were quantified before and after induction. The authors discovered that tyrosine hydroxylase (TH)+ sympathetic nerve fibers in both back and tail skin were significantly depleted by 6-OHDA treatment. In contrast, the number of tail epidermal melanocytes and CD8+ T cells was comparable between the two groups, before and after vitiligo induction. Contrary to the prevailing hypothesis (1), they reported that sympathetic nerve activity did not affect vitiligo progression.
2 Discussion
Although groundbreaking in its contribution, we identified some limitations in the study. First, although their melanoma-Treg-induced vitiligo mice indeed showed reduced numbers of melanocytes and CD8+ T cells, photographic evidence of white or gray skin and hair is necessary to satisfy the critical diagnostic criteria for observable hypopigmented lesions and to validate the authenticity of this model.
Importantly, this model depletes both Tregs and other CD4+ T cells such as helper T (Th)1 cells, making it unsuitable for a CD4+-related study (2). Consequently, this model omits immune responses mediated by Th1 and Th17, which directly contribute to melanocyte destruction through interferon (IFN)-γ and interleukin (IL)-17 (3). While this model emphasizes CD8+ T cells, reflecting their direct killing effect and the efficacy of current targeted treatment, it overlooks the indispensable role of CD4+ T cells in immune regulation. This restriction may have led to a skewed interpretation of the results and a potentially biased conclusion.
A previous study demonstrated that stress-triggered sympathetic nerve activation leads to hair graying by depleting melanocyte stem cells (MeSCs), and identified sympathetic nerve activation as the critical step in this process, independent of immune-mediated mechanisms (4). To address the potential oversight of stress-related sympathetic nervous system involvement, we recommend incorporating stress induction into future experimental designs. Including a stress stimulus could help clarify whether sympathetic nerve activity plays a functional role in disease onset or severity in this model.
Furthermore, it has also been hypothesized that sympathetic nerves modulate MeSC activity, melanocyte migration, or pigment production under conditions independent of the hair cycle (4). It has been suggested that, while MeSCs may be depleted, differentiated melanocytes and melanin synthesis are not directly affected, implying that differentiated melanocytes might not decline immediately following MeSC loss. When determining the optimal time point to quantify melanocytes, this delayed effect should be considered. Repeated measurements at multi-day intervals could help capture dynamic changes more accurately and improve the reliability of the analysis.
To investigate the potential role of the sympathetic nervous system in vitiligo development through neurotransmitter signaling mechanisms, particularly involving norepinephrine, a final analysis should extend beyond existing cell quantification to include measurements of circulating and local neurotransmitter levels.
Regarding the experimental design, adding a sympathetic nerve activation group using beta-adrenergic agonists, in contrast to the existing depletion group, may facilitate a more accurate assessment of the role of the sympathetic nervous system in vitiligo. Finally, to exclude false-negative results and confirm the validity of the experimental system, we recommend that the authors consider including another positive control group. For example, treatment with IFN-γ or tumor necrosis factor-alpha (TNF-α), both of which are known to exacerbate vitiligo (5), could serve as positive controls. Additionally, should circumstances permit, augmenting the sample size of mice would enhance statistical power and improve the robustness of the findings.
In summary, we hope that our feedback on this creative, pioneering study of vitiligo pathogenesis, particularly our suggestions regarding experimental timing and optimization of the modeling framework, will help inform and inspire future research endeavors in this field.
Author contributions
YP: Data curation, Formal analysis, Writing – original draft. TW: Conceptualization, Funding acquisition, Supervision, Writing – review & editing.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This study was supported by the National High-Level Hospital Clinical Research Funding (2022-PUMCH-B-092, to Tao Wang), the Beijing Municipal Natural Science Foundation (Z210017, to Tao Wang), the Beijing Key Clinical Specialty Construction Project, and the National Key Clinical Specialty Project of China.
Acknowledgments
We thank Michelle Kahmeyer-Gabbe, PhD, from Liwen Bianji (Edanz) (http://www.liwenbianji.cn) for editing the English text of a draft of this manuscript.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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The author(s) declare that no Gen AI was used in the creation of this manuscript.
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References
1. Hu Z, Chen T, Chen D. Local sympathetic nerve depletion does not alter vitiligo progression in a mouse model. Front Med. (2025) 12:1466996. doi: 10.3389/fmed.2025.1466996
2. Chen D, Xu Z, Cui J, Chen T. A mouse model of vitiligo based on endogenous auto-reactive CD8 + T cell targeting skin melanocyte. Cell Regen. (2022) 11:31. doi: 10.1186/s13619-022-00132-9
3. Hlaca N, Zagar T, Kastelan M, Brajac I, Prpic-Massari L. Current concepts of vitiligo immunopathogenesis. Biomedicines. (2022) 10:1639. doi: 10.3390/biomedicines10071639
4. Zhang B, Ma S, Rachmin I, He M, Baral P, Choi S, et al. Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells. Nature. (2020) 577:676–81. doi: 10.1038/s41586-020-1935-3
Keywords: skin disease, vitiligo, sympathetic nerve, commentary, mouse model
Citation: Peng Y and Wang T (2025) Commentary: Local sympathetic nerve depletion does not alter vitiligo progression in a mouse model. Front. Med. 12:1590092. doi: 10.3389/fmed.2025.1590092
Received: 08 March 2025; Accepted: 11 July 2025;
Published: 28 July 2025.
Edited by:
Vishal Thakur, All India institute of Medical Sciences, IndiaReviewed by:
Jianru Chen, Fourth Military Medical University, ChinaCopyright © 2025 Peng and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Tao Wang, d2FuZ3Rhb3B1bWNoQDEyNi5jb20=